The etiologies of bone disease are multifactorial. For example, evidence indicates a clear relation between both reduced bone perfusion and bone arteriolar function and diminished bone mass with aging, a global health concern. Thus, perhaps pharmaceutical interventions can be directed toward non-skeletal tissues. Parathyroid hormone (PTH) augments bone mass; however, it is also modulates vascular function. When given intermittently, PTH reduces the distance between blood vessels and sites of bone formation (i.e., osteoid surfaces) and it augments vasodilation of the femoral principal nutrient artery (PNA), the primary conduit for blood flow to long bones. Interestingly, co-administration of an anti-vascular endothelial growth factor (VEGF) antibody (Ab) prevented the relocation of bone blood vessels, inhibited the enhanced vasodilator function and blunted the bone accrual associated with PTH; highlighting the importance of VEGF signaling. The spatial location of bone blood vessels is vital for bone formation. Since vascular- osteoid separation decreased under conditions of PTH-induced bone accrual, perhaps this separation increases as a function of age; contributing to bone loss. Thus, age-related osteoporosis may derive a portion of its etiology from reduced bone blood flow and increased vascular-osteoid separation. The goals of this proposal are to examine whether intermittent PTH administration will diminish the presumed age-related augmented vascular-osteoid separation and restore the age-related declines in skeletal perfusion. A secondary goal is to determine whether these vascular alterations are regulated by VEGF. Analyses will be made among male Fischer-344 rats: 1) young, 2) old, 3) young+PTH, 4) old+PTH, 5) young+PTH+anti-VEGF Ab and 6) old+PTH+anti-VEGF Ab. Micro-CT and bone histomorphometry will assess bone microarchitecture, bone static and dynamic properties, bone vascular density and vascular-osteoid separation. Finally, in vivo bone blood flow measurements will be analyzed by injection of radiolabeled microspheres into the circulation. Findings will provide novel information concerning the spatial distribution of the bon blood vessels as a function of age, bone remodeling and mass and drug intervention. Further, the presumed vascular mechanisms of PTH-induced bone accrual can be observed concurrent to alterations in bone microarchitectural and bone static and dynamic properties. The proposed studies will mechanistically assess the role of VEGF and lay the groundwork for future studies examining the use of such pharmacological agents on bone cellular metabolism and vascular function concurrently.